(T1357) Deciphering Endothelial and Mesenchymal Organ Specification in Vascularized Lung and Intestinal Organoids

Abstract: To explore the co-development of vasculature, mesenchyme, and epithelium crucial for authentic organogenesis and organotypic characteristics acquisition, we developed a human pluripotent stem cell-derived organoid system encompassing lung or intestinal epithelium surrounded by organotypic mesenchyme and vasculature. Mesoderm-endoderm co-differentiation, which is essential for subsequent gut tube organoid vascularization, was exclusively modulated by BMP. Simultaneously, the BMP signal also dictated anterior-posterior gut specification prior to the conventional primitive gut tube formation period. Single-cell RNA-seq analysis uncovered organ-specific endothelium and mesenchyme from vascularized organoids, identifying key ligands driving endothelial specification in lung and intestine. Organotypic endothelium exerted tissue-specific barrier function, enhanced epithelium maturation, and supported alveolar structure formation on bioengineered scaffolds. Upon transplantation in mice, these organoids matured further, forming perfusable organ-specific human capillaries. The spatial transcriptomic analysis confirmed the similar spatial organization of ligand-receptor pairs in the transplanted vascularized lung organoid compared to those found in human fetal lung tissues, which facilitated the characterization of lung endothelium and epithelium. Additionally, our model recapitulated abnormal endothelial-epithelial crosstalk in patients with FOXF1 deletion or mutations. Multilineage organoids provide a unique platform to study developmental cues guiding endothelial and mesenchymal cell fate determination, and investigate intricate cell-cell communications in human organogenesis and disease.

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